Multi chamber flexible bag and methods of using same

ABSTRACT

A method of preparing a pharmaceutical product in a single multiple chamber flexible bag. A pharmaceutical product is introduced in a liquid state into a first chamber of the flexible bag through a first port. The pharmaceutical product is lyophilized within the first chamber of the flexible bag to provide a lyophilized pharmaceutical product. The flexible bag has a second chamber and the first chamber and the second chamber are separated by a breakable seal. The second chamber further includes a reconstituting solution for reconstituting the lyophilized pharmaceutical product in the first chamber. A user may apply pressure to the flexible bag to break the seal and mix the lyophilized pharmaceutical product and the reconstituting solution to order to administer the pharmaceutical product to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/249,347, filed Jan. 16, 2019, which is a continuation-in-part of U.S.patent application Ser. No. 15/609,870, filed May 31, 2017. Bothapplications are incorporated in their entirety by reference thereto.

BACKGROUND Field of the Invention

Embodiments of the invention generally relate to a multi chamberflexible bag for use with pharmaceutical products. More particularly,embodiments relate to methods, systems, and apparatuses formanufacturing, storing, reconstituting, diluting, and administering oflyophilized pharmaceutical products to a patient.

Background

Lyophilization or freeze-drying is a technique applied to pharmaceuticalproducts. Through lyophilization, the shelf-life of pharmaceuticalproducts that would have been minimal in a liquid state may be extendedand standardized. Lyophilization is the process of removing the liquidportion from a frozen sample by converting the liquid portion directlyinto vapor without the intermediate formation of the liquid. The mainsteps of lyophilizing are freezing (from a liquid state to a solidstate), primary drying (sublimation), and secondary drying (with hightemperatures for removing the non-frozen liquid).

BRIEF SUMMARY

The following presents a simplified summary of the present disclosure inorder to provide a basic understanding of some aspects described herein.This summary is not an extensive overview and is not intended toidentify key or critical elements or to delineate the scope of theclaims. The following summary merely presents various described aspectsin a simplified form as a prelude to the more detailed descriptionprovided below.

The present embodiments relate to processes, systems, and apparatusesfor lyophilizing a pharmaceutical product within a multi chamberflexible bag. The lyophilized pharmaceutical product may be stored andreconstituted within the same multi chamber flexible bag in which thepharmaceutical product was lyophilized. By lyophilizing, storing, andreconstituting the pharmaceutical product within the same bag, the bagacts a self-contained product that is ready to administer to a patientwithout having to include additional manipulation steps outside of themulti chamber flexible bag. The advantages of the multi chamber flexiblebag are a reduction in reconstitution time and error, avoidance ofaccidental exposure of health care workers during dilution,reconstitution, and handling of the pharmaceutical products resulting inan increase in compliance with regulations.

Aspects of the disclosure may include a method of preparing apharmaceutical product in a single multiple chamber flexible bag. Apharmaceutical product is introduced in a liquid state into a firstchamber of the flexible bag through a first port. The pharmaceuticalproduct is lyophilized within the first chamber of the flexible bag toprovide a lyophilized pharmaceutical product. The flexible bag has asecond chamber and the first chamber and the second chamber areseparated by a breakable seal. The second chamber further includes areconstituting solution for reconstituting the lyophilizedpharmaceutical product in the first chamber. A user may apply pressureto the flexible bag to break the seal and mix the lyophilizedpharmaceutical product and the reconstituting solution to order toadminister the pharmaceutical product to a patient. Additional chambersmay also be used to form the bag. For example, a third or fourth chambermay be separated from one of the first and second chambers. The third orfourth chamber may be separated by a breakable seal or other means, forexample, a valve.

Another aspect of the disclosure may include a flexible pharmaceuticalbag with a first chamber configured to hold a lyophilized pharmaceuticalproduct and a second chamber separated from the first chamber. In someembodiments, the second chamber is configured to hold a reconstitutingsolution for reconstituting the lyophilized pharmaceutical product inthe first chamber. The bag may further include a seal disposed betweenthe first chamber and the second chamber that separates and seals thefirst chamber from the second chamber. A first port is attached to thefirst chamber, the first port configured to introduce a pharmaceuticalproduct into the first chamber and allow passage of water vapor from thepharmaceutical product during lyophilization of the pharmaceuticalproduct. The second chamber may include second port attached to thesecond chamber, the second port configured to introduce thereconstituting solution for reconstituting the lyophilizedpharmaceutical product in the first chamber. A health care worker maybreak the seal to mix the lyophilized pharmaceutical product and thereconstituting solution. The flexible pharmaceutical bag may alsoinclude a third chamber. The third chamber may be configured to hold asolution or other product. A second seal may be disposed between thethird chamber and one of the first and second chambers. Alternatively,the third chamber may be separated from one of the first and secondchambers by a valve. The valve may be a one-way valve and may have abreakable seal.

In another aspect of the invention, the bag may be fabricated from amaterial that is able to withstand autoclave sterilization at 121°Celsius and lyophilization at −55° Celsius.

BRIEF DESCRIPTION OF THE DRAWINGS

Some features herein are illustrated by way of example, and not by wayof limitation, in the accompanying drawings. In the drawings, likenumerals reference similar elements between the drawings.

FIG. 1 illustrates a multi chamber flexible bag for holding alyophilized pharmaceutical product and a corresponding reconstitutingsolution according to an embodiment.

FIG. 2 illustrates a cross-sectional view of the multi chamber flexiblebag taken along cross-sectional line 2-2 of FIG. 1 according to anembodiment.

FIG. 3 illustrates a flowchart of a method for preparing apharmaceutical product in a multi chamber flexible bag according to anembodiment.

FIG. 4 illustrates a flowchart of a method for preparing apharmaceutical product in a multi chamber flexible bag according to anembodiment.

FIG. 5 illustrates a multi chamber flexible bag with a pharmaceuticalproduct in a first chamber of the multi chamber flexible bag accordingto an embodiment.

FIG. 6 illustrates a multi chamber flexible bag with a lyophilized(freeze-dried) pharmaceutical product in a first chamber of the multichamber flexible bag according to an embodiment.

FIG. 7 illustrates a multi chamber flexible bag with a lyophilized(freeze-dried) pharmaceutical product in a first chamber of the multichamber flexible bag and a reconstituting solution in a second chamberof the multi chamber flexible bag according to an embodiment.

FIG. 8 illustrates a multi chamber flexible bag with a lyophilized(freeze-dried) pharmaceutical product in a first chamber of the multichamber flexible bag and a reconstituting solution in a second chamberof the multi chamber flexible bag with pressure applied to the secondchamber to break a seal in order to mix the lyophilized pharmaceuticalproduct and the reconstituting solution according to an embodiment.

FIG. 9 illustrates a multi chamber flexible bag with a reconstitutedpharmaceutical product in operation according to an embodiment.

FIG. 10 illustrates a multi chamber flexible bag for holding alyophilized pharmaceutical product according to an embodiment.

FIG. 11 illustrates a multi chamber flexible bag for holding alyophilized pharmaceutical product according to an embodiment.

FIG. 12 illustrates a multi chamber flexible bag for holding alyophilized pharmaceutical product according to an embodiment.

FIG. 13 illustrates a multi chamber flexible bag for holding alyophilized pharmaceutical product according to an embodiment.

DETAILED DESCRIPTION

The present inventions will now be described in detail with reference toembodiments thereof as illustrated in the accompanying drawings, inwhich like reference numerals are used to indicate identical orfunctionally similar elements. References to “one embodiment”, “anembodiment”, “an example embodiment”, etc., indicate that the embodimentdescribed may include a particular feature, structure, orcharacteristic, but every embodiment may not necessarily include theparticular feature, structure, or characteristic. Moreover, such phrasesare not necessarily referring to the same embodiment. Further, when aparticular feature, structure, or characteristic is described inconnection with an embodiment, it is submitted that it is within theknowledge of one skilled in the art to affect such feature, structure,or characteristic in connection with other embodiments whether or notexplicitly described.

The following examples are illustrative, but not limiting, of thepresent inventions. Other suitable modifications and adaptations of thevariety of conditions and parameters normally encountered in the field,and which would be apparent to those skilled in the art, are within thespirit and scope of the inventions.

The present embodiments relate to processes, systems, and apparatusesfor lyophilizing a pharmaceutical product within a multi chamberflexible bag. The lyophilized pharmaceutical product may be stored andreconstituted within the same multi chamber flexible bag in which thepharmaceutical product was lyophilized. By lyophilizing, storing, andreconstituting the pharmaceutical product within the same bag, the bagacts a self-contained product that is ready to administer to a patientwithout having to include additional manipulation steps outside of themulti chamber flexible bag. The advantages of the multi chamber flexiblebag are a reduction in reconstitution time and error, avoidance ofaccidental exposure of health care workers during dilution,reconstitution, and handling of the pharmaceutical products resulting inan increase in compliance with regulations.

The multi chamber flexible bag may be used with a number ofpharmaceutical products. For example, the multi chamber flexible bag maybe advantageous for the preparation of cytotoxic drugs, anti-neoplastic,immunomodulatory, and/or chemotherapeutic products. Examples ofcytotoxic compounds and antineoplastic compounds include at leastazacytidine, belinostat, bendamustine, brentuximab vedotin, bleomycin,bortezomib, busulfan, carboplatin, carmustine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine,deferoxamine, doxorubicin, epirubicin hydrochloride, fludarabine,fotemustine, fulvestrant, gemcitabine, idarubicin, ifosfamide,irinotecan hydrochloride, ixabepilone, melphalan, methotrexate,oxaliplatin, paclitaxel, pemetrexed, pentostatin, raltitrexed,romidepsin, temozolomide, thiotepa, topotecan, trabectedin, trastuzumab,and vinblastine. Cytotoxic drugs describe a group of medicines thatcontain chemicals which are toxic to cells, preventing their replicationor growth, and are used to treat cancer and other disorders. Cytotoxicdrugs are commonly manufactured in lyophilized form to extend the shelflife of the drug, ease transportation of the drugs, and for the healthand well-being of heath care workers who handle and administer cytotoxicdrugs to patients. The present application may also be applicable toother products that may be lyophilized such as, nutritional elements,nutraceuticals, plasma, blood products, and blood derivatives.

Other pharmaceutical products may be used with the multi chamber bag.Examples of antibiotic compounds include at least amikacin,erythromycin, and mitomycin. Examples of antimicotic compounds includeat least amphotericin, anidulafungin, flucytosine, fluconazole,isavuconazonium sulfate, micafungin, rifampicin, and voriconazole.Examples of antiviral compound include at least aciclovir andganciclovir. Examples of beta-blocking compounds include at leastesmolol. Example of detoxifying compounds include at least amifostine,dexrazoxane, and levoleucovorin calcium. Example of immunomodulatingcompounds include at least abatacept, aldesleukin, belimumab, degarelix,infliximab, mifamurtide, and tasonermin. Examples of antibacterialcompounds include at least amoxicillin, ampicillin,ampicillin/sulbactam, azithromycin, aztreonam, cefuroxime,clarithromycin, daptomycin, caspofungin, cefalotin, cefamandole,cefotaxime, cefazolin, cefepime, ceftazidime, cefoxitin, ceftobiprolemedocaril, cefatoroline fosamil, chloramphenicol, dalbavancinhydrochloride, delfoprostin/quinuprostin, doripenem, ertapenem,gentamicin, imipenem/cilastatin, meropenem, oritavancin diphosphate,oxacillin, piperacillin/tazobactam, pentamidine, tedizolid phosphate,teicoplanin, telavancin hydrochloride, tigecycline, and vancomycin.Examples of anti-inflammatory compounds include at least diclofenac,ibuprofen, and indomethacin. Examples of anti-haemorrhagic compoundsinclude at least alpha 1 antitrypsin, coagulation factor VII,coagulation factor VIII, coagulation factor IX, human anti-hemophilicprothrombin complex, gabexate, moroctocog alfa, nonacog alfa, octocogalfa, and simoctocog alfa. Examples of antiemetic compounds include atleast fosaprepitant. Examples of antithrombotic compounds include atleast alteplase, bivalirudin, cangrelor, epoprostenol, and urokinase.Examples of proton pumps inhibitors include at least esomeprazole,omeprazole, and pantoprazole. Examples of anxiolytics compounds includeat least lorazepam. Examples of calcium channel blocker compoundsinclude at least diltiazem. Examples of antidotes compounds include atleast pralidoxime. Examples of enzymes include at least algasidase beta,alglucosidase alfa, alpha-glucosidase, beta-glucosidase,alpha-galactosidase, beta-galactosidase, taliglucerase alfa, andvelaglucerase alfa. Examples of hormones include at least glucagone,levothyroxine sodium, menotrophin, somatorelin, somatostatin,somatropin, and urofollitropin. Examples of antineovascularizationcompounds include at least verteporfin. Examples of compounds fortreatment of bone diseases include at least zoledronic acid. Examples ofcompounds for cardiac therapy include at least nesiritide. Examples ofhormones for diagnostic use include at least secretin and somatorelin.

Due to the toxicity of cytotoxic drugs, occupational exposure to healthcare workers presents significant risks, especially when controlmeasures are inadequate. Control measures may include the use ofprotective clothing, protective devices, and protective equipment toavoid accidental exposure. Health care workers may be exposed tocytotoxic drugs by inhalation, dermal contact, or orally.

Inhalation exposure may occur via droplets, particulate, and vapors whenan aerosol is created. Because the molecular size of vapors is smallerthan particulates, biological safety cabinets may not be able to removethe vapors from the atmosphere. Dermal exposure may occur when healthcare workers touch contaminated surfaces during the preparation,administration, or disposal of drugs. Contamination may be found on worksurfaces situated throughout a hospital medication system (process flowof cytotoxic drugs at a facility from initial delivery to final wastedisposal) and is not strictly limited to the drug preparation and drugadministration areas. Oral exposure may occur from hand-to-mouthcontact.

Embodiments of the current disclosure are directed to a bag that isconfigured to lyophilize a pharmaceutical product within a chamber ofthe bag. In some embodiments, the bag is configured to hold areconstituting solution in another chamber of the bag, and allow mixingof the lyophilized pharmaceutical product with the reconstitutingsolution in the bag. In some embodiments, the bag is configured to allowadministration of the reconstituted pharmaceutical product to a patientfrom the bag. In some embodiments, the bag may advantageously maintainthe pharmaceutical product within the bag without additionalmanipulation steps of the pharmaceutical product outside of the bagafter the pharmaceutical product has been introduced into the bag.

FIG. 1 illustrates an exemplary embodiment of a multi chamber flexiblebag 100. While FIG. 1 illustrates bag 100 with two chambers, but thepresent disclosure is not so limited. Bag 100 may have multiple chambersfor holding various components and solutions. Bag 100 may include anouter seal 102 that extends around the perimeter of bag 100. Outer seal102 may provide an oxygen and water vapor seal to avoid contamination ofthe contents (e.g., pharmaceutical products, reconstituting solution,etc.) stored within bag 100. Outer seal 102 defines the outer limits ofa first chamber 110 and a second chamber 120. In one embodiment, asshown in FIG. 1, bag 100 includes a first chamber 110 for holding andlyophilizing a pharmaceutical product. First chamber 110 may include aport 112 for introducing the pharmaceutical product into first chamber110 in a sterile manner. Port 112 may also be used in the lyophilizationprocedure to enable that passage of water vapor from the pharmaceuticalproduct. First chamber 110 may have a volume suitable for lyophilizing apharmaceutical product. For example, first chamber 110 may have a volumeof 50 ml. Other suitable volumes may be used.

Bag 100 may further include a second chamber 120 for holding areconstituting solution or solvent. Second chamber 120 may include oneor more ports for introducing the reconstituting solution into secondchamber 120 and for administrating the reconstituted pharmaceuticalproduct to a patient. For example, port 122 may be used for introducingthe reconstituting solution into second chamber 120 in a sterile manner.Second chamber 120 may further include multiple administration ports 124and 126. The types of ports 124 and 126 attached to second chamber 120may be based on patient or health care worker preference. In operation,for example, administration ports 124 and 126 may be used by a healthcare worker to administer the reconstituted pharmaceutical product to apatient, for example by intravenous therapy. In another example, port124 may attach to standard IV equipment. The dose of the reconstitutedpharmaceutical product may be based on specific characteristics of thepatient. For example, the body weight of the patient may be consideredwhen adjusting the dose before the reconstituted pharmaceutical productis administered to the patient through port 126. As will becontemplated, bag 100 may be used by any suitable individual, however,for simplicity, the disclosure will refer to users as health careworkers. In one embodiment, second chamber 120 may be sized relative tofirst chamber 110 in order to provide sufficient volume ofreconstituting solution to reconstitute the pharmaceutical product infirst chamber 110. In one embodiment, second chamber 120 may have avolume greater than the volume of first chamber 110. For example, secondchamber 120 may have a volume of 500 ml. Other suitable volumes may beused.

Bag 100 may further include a seal 130 that separates and defines firstchamber 110 and second chamber 120. Seal 130 maintains the integrity ofthe lyophilized pharmaceutical product and the reconstituting solutionand prevents the unintended passage of the reconstituting solution tothe lyophilized pharmaceutical product, or vice versa, before anappropriate time. FIG. 1 illustrates seal 130 as extending the length ofbag 100, from a top of bag 100 to a bottom of bag 100. Alternatively,seal 130 may only extend a portion of the length of bag 100. In oneembodiment, for example, as shown in FIGS. 5-7, seal 130 may extend fromouter seal 102 of bag 100 to an inner seal 104. However, the geometry ofseal 130 is not so limited. In another embodiment, seal 130 may becurved.

In one embodiment, bag 100 may be fabricated from a tubular film or cutas a double wound film at a desired width. As shown, for example, inFIG. 2, bag 100 may include a front film 210 and a back film 220 thatare joined together. Front film 210 and back film 220 may be joinedtogether at the edges to create outer seal 102. Outer seal 102 may becreated by using a predetermined temperature and a predetermined amountof pressure to seal front film 210 and back film 220. Outer seal 102 ismade such that it is not breakable, at least during normal operation. Inaddition, front film 210 and back film 220 may be joined together withinouter seal 102 to define seal 130. Seal 130 is created by using apredetermined temperature and a predetermined amount of pressure to sealfront film 210 and back film 220. In this manner, seal 130 may define aconnection between front film 210 and back film 220. Seal 130 is createdto be breakable. Front film 210 and back film 220 may be joined togetherthrough heat sealing, RF welding, molding, and other suitabletechniques. FIG. 2 illustrates a cross-sectional view of bag 100 alongcross-sectional line 2-2 of FIG. 1. Cross-sectional line 2-2 intersectsouter seal 102, first chamber 110, seal 130, and second chamber 120.

In one embodiment, seal 130 may be fabricated from the same material ofthe overall bag 100 (e.g., front film 210 and back film 220). Becausebag 100 and seal 130 are fabricated from the same material, no othermaterial comes in contact with the pharmaceutical product in order toavoid contamination. Seal 130 may be placed in various locations on bag100 to form at least two chambers within bag 100. If bag 100 includesadditional chambers, bag 100 may include additional seals to separatethe chambers and define their geometry. Seal 130 may be broken byapplying a predetermined amount of pressure to bag 100. For example,pressure may be applied to second chamber 120 by the health careworker's hand. The amount of pressure to break seal 130 may range from30-70 Kgf. In this manner, seal 130 is a breakable seal. The pressuremay be applied by a health care worker when the health care worker isready to administer the pharmaceutical product to the patient, in orderto extend the shelf life of the lyophilized pharmaceutical product, asshown for example in FIG. 8. Once seal 130 has been broken, thereconstituting solution mixes with the freeze-dried pharmaceuticalproduct to produce a reconstituted pharmaceutical product. Seal 130 mayhave a width between 5 to 15 mm or 8 and 12 mm. Seal 130 is stronger asthe width of seal 130 increases and requires more pressure to break seal130. Seal 130 is designed to withstand a predetermined amount ofpressure before breaking. For example, during transport of the flexiblebag, seal 130 may undergo pressure and/or force during normal transportprocedures. Seal 130 is designed to maintain its integrity under smalleramounts of pressure (e.g., less than 30 Kgf) so seal 130 does not breakduring transport until a predetermined amount of pressure is applied.

Seal 130 may be joined in such a way as to create a weak point 132 inseal 130 so that weak point 132 breaks first when pressure is applied tobag 100. Seal 130 may include multiple weak points 132 along the lengthof seal 130. Weak point 132 may have a width smaller than the rest ofseal 130. For example, weak point 132 may have a width of 5 to 8 mm.

In one embodiment, seal 130 may include a valve between first chamber110 and second chamber 120 to prevent the passage of reconstitutingsolution until the health care worker is ready to administer thepharmaceutical product.

Bag 100 may be fabricated from a material that provides an oxygen andwater vapor barrier. The material may also be capable of withstandingthe extreme temperatures of autoclave sterilization and lyophilizing.For example, the material for bag 100 is capable of withstandingautoclave sterilization at 121° Celsius and freeze dying at −55° Celsiuswithout the material breaking down and leaching into the pharmaceuticalproduct and reconstituting solution within the bag. The material for thebag 100 is capable of withstanding extreme temperature up to −80°Celsius. Other aspects of the material may include flexibility so thatbag 100 is shatter-proof and is easy to transport. The material may alsobe transparent so that the health care worker may easily see within bag100 to identify that lyophilizing and reconstitution has occurred, andsee how much reconstituted pharmaceutical product is still in bag 100during administration of the pharmaceutical product.

In one embodiment, bag 100 comprises polyolefin/styrene-block copolymerbased film. The material used for bag 100 meets all of the requirementsrequired by the United States and European pharmaceutical regulation,SFDA Standard for “Registration standard for imported pharmaceuticalpackaging materials” (China), International Standard ISO 15747 “Plasticscontainers for intravenous injection”, and International Standard ISO10993 “Biological Evaluation of medical devices.”

Ports 112, 122, 124, and 126 may each include a connector 114 and a tube116. Connectors 114 enable the sealing of ports 112, 122, 124, and 126and enable health care workers and/or the manufacture to attachequipment for introducing solutions into the chamber and for extractingsolutions from the chamber. A variety of different types of connectors114 may be used to expand the type of equipment that may be utilizedwith connectors 114. Tubes 116 enable the passage of liquid or gas fromthe outside environment to the chambers, or vice versa. Tubes may befabricated from a polyolefin/styrene block copolymer that is coextrudedat a desired dimension. Tubes may also be fabricated from any othersuitable material. Connections may be fabricated from polypropylene andpolycarbonate or any other suitable material. Ports 112, 122, 124, and126 are capable of withstanding autoclave sterilization at 121° Celsiusand freeze dying at −55° Celsius or up to −80° Celsius. The outerdiameter of tubes may be 8.1 mm 0.08 mm and the tube thickness may be1.0 mm±0.08 mm. In one embodiment, the material used for ports 112, 122,124, and 126 meets all of the requirements required by the United Statesand European pharmaceutical regulation, SFDA Standard for “Registrationstandard for imported pharmaceutical packaging materials” (China),International Standard ISO 15747 “Plastics containers for intravenousinjection”, and International Standard ISO 10993 “Biological Evaluationof medical devices.”

Bag 100 may further include a label area 140 that is used for providingaccessible information on bag 100, such as, for example, the necessaryinformation as may be required by law. In addition, the label area 140may include barcodes, QR codes, RFIDs, etc. for easy identification ofthe pharmaceutical product, dosage details, warnings, possible adversereactions, patient information, etc.

Bag 100 may further include a through hole 150 in outer seal 102.Through hole 150 may be utilized by the health care worker to attachedbag 100 to an IV stand for ease of administering the reconstitutedpharmaceutical product to a patient.

FIG. 3 illustrates a flowchart for a method of preparing thepharmaceutical product with a single bag 100, according to anembodiment. The method includes the steps of S310 introducing thepharmaceutical product into first chamber 110, S320 lyophilizingpharmaceutical product in first chamber 110, S330 introducingreconstituting solution into second chamber 120, and S340 breaking seal130 and mixing reconstituting solution and lyophilized pharmaceuticalproduct. Each step will be explained in further detail below.

In step S310, a predetermined amount of the pharmaceutical product 500of a known concentration is introduced into first chamber 110 of bag 100through port 112 in a sterile manner. For example, pharmaceuticalproduct may pass through a sterile filter. The amount and concentrationof the pharmaceutical product is needed for calculating the dilution andreconstitution of the pharmaceutical product after lyophilization. FIG.5 illustrates the pharmaceutical product 500 in first chamber 110. Arrow502 indicates the passage of pharmaceutical product 500 through port112. Pharmaceutical product 500 may comprise a liquid state. Once thepharmaceutical product 500 is within first chamber 110, port 112 isclosed with a sterile stopper and bag 100 may be placed in alyophilizer. Sterile stopper does not completely close port 112 butleaves the necessary space to permit the passage of vapor during thelyophilization process. Bag 100 is configured to withstand theconditions of lyophilizer (e.g., temperature, pressure, etc.).

In step S320, bag 100, along with other bags that also containpharmaceutical product 500 as necessary, are placed on a tray within thelyophilizer. Bag 100 may be oriented in a vertical, or slightly angledvertical position, with port 112 at the top and the bottom of bag 100may be secured to the tray. With port 112 at the top, port 112 enablesthat passage of water vapor from the pharmaceutical product during thelyophilization procedure and avoids spillage of the pharmaceuticalproduct during lyophilization. When all of the bags are in a secureposition, the freeze-drying process may begin. Table 1, provided below,provides data related to an exemplary lyophilization process forfreeze-drying the pharmaceutical product. The temperatures, time, andpressures may vary in accordance with the type of pharmaceutical productplaced in bag 100. FIG. 6 illustrates a bag 100 with the lyophilizedpharmaceutical product 600 after the lyophilization process is complete.

TABLE 1 Time Temperature (hour:minute) Pressure Freezing - shelves −50°C.-−42° C.  2:00 atm cooling Freezing - shelves −50° C.-−42° C.  6:00holding Primary drying (shelves −5° C. 10:00 50-400 heating) Primarydrying (shelves −5° C. 20:00 μbar holding) Secondary drying (shelves 10°C. 10:00 heating) Secondary drying (shelves 10° C.  6:00 holding)Secondary drying (shelves 15° C.  1:00 heating) Secondary drying(shelves 15° C. 10:00 holding)

In S330, a predetermined amount of a sterile reconstituting solution isaseptically introduced into second chamber 120 through port 122. Theamount of reconstituting solution introduced into second chamber 120 isdependent on the desired dilution of pharmaceutical product 500 foradministration to a patient. FIG. 7 illustrates reconstituting solution700 in second chamber 120. Arrow 702 indicates the passage ofreconstituting solution 700 through port 122. Reconstituting solution700 may be a sterile 0.9% saline solution, or any other suitablesolution for reconstitution and dilution of pharmaceutical product 500.Other examples of reconstituting solution include water, alcohol-basedsolutions, etc. Examples of dilution solutions include saline solution,glucose solution, Ringer solution, etc.

In one embodiment, step S330 may be performed when bag 100 is in aplurality of different locations. For example, bag 100 may be removedfrom the lyophilizer and reconstituting solution 700 may be introducedin second chamber at a preparation facility and then stored andtransported under refrigerated and sterile conditions.

In S340, a health care worker may mix the reconstitution solution 700with lyophilized pharmaceutical product 600 to reconstitute and properlydilute lyophilized pharmaceutical product 600 to a reconstitutedpharmaceutical product 900. The health care worker may break seal 130 byapplying pressure by hand to bag 100, for example to second chamber 120,which is illustrated in FIG. 8. Because bag 100 is flexible, when thehealth care worker presses on the bag, pressure is created within bag100 and is applied to seals 102, 104, and 130. Outer seal 102 and innerseal 104 are stronger than seal 130 that separates first chamber 110 andsecond chamber 120 so that seal 130 breaks before outer seal 102 andinner seal 104.

When a predetermined amount of pressure (e.g., 30-70 kgf) is applied bag100, seal 130 breaks and first chamber 110 and second chamber 120 becomea single chamber for mixing lyophilized pharmaceutical product 600 withreconstituting solution 700. In one embodiment, the health care workermay produce more pressure by applying pressure on second chamber 120rather than first chamber 110 because second chamber contains a liquidand first chamber 110 contains a lyophilized product and a gas. Inaddition, seal 130 may include weak point 132 to initiate the breakingof seal 130.

FIG. 4 illustrates another exemplary flowchart for a method of preparingthe pharmaceutical product with a single bag 100. The method includesthe steps of S410 introducing the pharmaceutical product into firstchamber 110, S420 lyophilizing pharmaceutical product in first chamber110, S430, closing port 112 to first chamber 110, S440 introducingreconstituting solution into second chamber 120, S450 breaking seal 130and mixing reconstituting solution and lyophilized pharmaceuticalproduct, and S460 administering reconstituted pharmaceutical product topatient. Each step will be explained in further detail below.

Steps S410, S420, S440, and S450 are similar to steps S310, S320, S330,and S340 as explained above in regard to the method in FIG. 3. In S430,once the pharmaceutical product 500 is lyophilized, port 112 may bepermanently closed to maintain the integrity of lyophilizedpharmaceutical product 600. For example, the outside environment, e.g.,oxygen, water vapor, etc., may contaminate lyophilized pharmaceuticalproduct 600, so sealing first chamber 110 helps maintain the integrityof lyophilized pharmaceutical product 600. Port 112 may be sealed afterinsufflation of sterile gas. The lyophilization vacuum may be broken byan insufflation of sterile gas under slight vacuum and the gas isintroduced into first chamber 110. In one embodiment, the insufflationgas is nitrogen. If the pharmaceutical product is not sensitive tooxygen, compressed air may be used as the insufflation gas. This processmaintains the sterility of first chamber 110 and avoids the oxidation oflyophilized pharmaceutical product 600.

In S460, after the health care worker has reconstituted thepharmaceutical product 900, the health care worker may administerreconstituted pharmaceutical product 900 to a patient. Reconstitutedpharmaceutical product 900 may be administered in a number of ways. Forexample, FIG. 9 illustrates reconstituted pharmaceutical product 900being administered by way of intravenous therapy. Through hole 150 inbag 100 allows the health care worker to hang bag 100 from an IV standand administration ports 124 and 126 allow a health care worker attachedstandard IV equipment for treatment.

In addition, bag 100 may be sterilized in an autoclave at themanufacturing facility of the pharmaceutical product. The material ofbag 100 enables bag 100 to withstand autoclave sterilization at 121°Celsius.

FIG. 10 shows bag 100 according to some embodiments. Bag 100 has firstchamber 110 and second chamber 120. Additionally, bag 100 has a thirdchamber 160. Bag 100 may have more than three chambers. For example, bag100 may have four, five, or six chambers. FIG. 10 shows breakable seal130 separating first chamber 110 from second chamber 120. A secondbreakable seal 170 separates first chamber 120 from third chamber 160.In some embodiments, third chamber 160 is configured to hold anotherpharmaceutical product, saline solution, alcoholic solvent, or otherproducts.

FIG. 11 shows bag 100 according to some embodiments. Bag 100 has threechambers: first chamber 110, second chamber 120, and third chamber 160.Each chamber is separated by breakable seals 130, 170 from an adjacentchamber. FIG. 12 shows bag 100 according to some embodiments. As shownin FIG. 12, a port 172 may connect chambers of bag 100. For example, asshown in FIG. 12, port 172 connects second chamber 120 and third chamber160. Port 172 may be a valve, for example a one-way valve. In someembodiments port 172 may have a breakable valve that permanently opensin response to a pressure differential between the chambers. FIG. 13shows bag 100 according to some embodiments. As shown in FIG. 13, a port172 may connect chambers of bag 100. In this and other embodiments,there is no breakable seal as all chambers are connected by ports 172.

The method of lyophilizing, storing, and reconstituting a pharmaceuticalproduct within the same flexible bag may have one or more benefits. Forexample, bag 100 is a ready-to-administer product that needs littlemanipulation by the health care worker. The pharmaceutical product islyophilized which increases the shelf life of the pharmaceuticalproduct. The reconstituting solution is stored in the second chamberwhich is prepared for the proper dilution and reconstitution of thepharmaceutical product avoiding possible reconstitution and dilutioncalculation errors. Additional manipulation of the pharmaceuticalproduct outside the bag is avoided because the pharmaceutical productstays within the bag after it is introduced until the pharmaceuticalproduct is administered. Additional manipulation introduces thepossibility of product contamination and/or safety issues for healthcare workers, especially if the pharmaceutical product is a toxic drug,such as a cytotoxic drug. Possible contamination of the pharmaceuticalproduct is avoided by keeping the pharmaceutical product within a singlebag and sealing the first chamber from the outside environment.

Embodiments of the invention may be directed to a method of preparing apharmaceutical product in a multiple chamber flexible bag. The methodincluding introducing a pharmaceutical product in a liquid state into afirst chamber of the flexible bag through a first port and lyophilizingthe pharmaceutical product within the first chamber of the flexible bagto provide a lyophilized pharmaceutical product, wherein the flexiblebag has a second chamber and the first chamber and the second chamberare separated by a breakable seal.

In any of the various embodiments discussed herein, the method mayfurther include introducing a reconstituting solution into a secondchamber of the flexible bag.

In any of the various embodiments discussed herein, the method mayfurther include introducing a gas into the first chamber and sealing thefirst port after the pharmaceutical product in the first chamber hasbeen lyophilized.

In any of the various embodiments discussed herein, the method mayfurther include applying a predetermined amount of pressure to theflexible bag to break the breakable seal between the first chamber andthe second chamber and mixing the reconstituting solution with thelyophilized pharmaceutical product in the first chamber to create areconstituted pharmaceutical product.

In any of the various embodiments discussed herein, the method mayfurther include administering the final pharmaceutical product to apatient through an administration port disposed in the flexible bag.

In any of the various embodiments discussed herein, the breakable sealis formed between the first chamber and the second chamber by joining afront surface of the flexible bag and the back surface of the flexiblebag.

In any of the various embodiments discussed herein, the breakable sealcomprises a weak point where the breakable seal is not as wide as therest of the breakable seal and the breaking of the breakable sealinitiates at the weak point when pressure is applied to the flexiblebag.

In any of the various embodiments discussed herein, the pharmaceuticalproduct is a cytotoxic drug.

In any of the various embodiments discussed herein, the cytotoxic drugis selected from the group consisting of: azacytidine, belinostat,bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan,carboplatin, carmustine, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin,epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant,gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride,ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel,pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide,thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine.

In any of the various embodiments discussed herein, the reconstitutingsolution is a 0.9% saline solution.

In any of the various embodiments discussed herein, the bag isfabricated from a polyolefine/styrene-block copolymer based film.

Some embodiments may include a flexible pharmaceutical bag that includesa first chamber configured to hold a lyophilized pharmaceutical product,a second chamber separated from the first chamber, the second chamberconfigured to hold a reconstituting solution for reconstituting thelyophilized pharmaceutical product in the first chamber, a seal disposedbetween the first chamber and the second chamber that separates andseals the first chamber from the second chamber and a first portattached to the first chamber, the first port configured to introduce apharmaceutical product into the first chamber and allow passage of watervapor from the pharmaceutical product during lyophilization of thepharmaceutical product.

In any of the various embodiments discussed herein, the bag may furtherinclude a second port attached to the second chamber, the second portconfigured to introduce the reconstituting solution to the secondchamber for reconstituting the lyophilized pharmaceutical product in thefirst chamber.

In any of the various embodiments discussed herein, the seal is aconnection between a front surface of the pharmaceutical bag and a backsurface of the pharmaceutical bag.

In any of the various embodiments discussed herein, the seal extends thelength of the pharmaceutical bag between the first chamber and thesecond chamber.

In any of the various embodiments discussed herein, a predeterminedamount of pressure applied to the pharmaceutical bag breaks the seal andconnects the second chamber to the first chamber.

In any of the various embodiments discussed herein, the seal furthercomprises a weak point to provide an initial breaking point when apredetermined amount of pressure is applied to the pharmaceutical bag.

In any of the various embodiments discussed herein, the pharmaceuticalproduct is a cytotoxic drug.

In any of the various embodiments discussed herein, the cytotoxic drugis selected from the group consisting of: azacytidine, belinostat,bendamustine, brentuximab vedotin, bleomycin, bortezomib, busulfan,carboplatin, carmustine, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, decitabine, deferoxamine, doxorubicin,epirubicin hydrochloride, fludarabine, fotemustine, fulvestrant,gemcitabine, idarubicin, ifosfamide, irinotecan hydrochloride,ixabepilone, melphalan, methotrexate, oxaliplatin, paclitaxel,pemetrexed, pentostatin, raltitrexed, romidepsin, temozolomide,thiotepa, topotecan, trabectedin, trastuzumab, and vinblastine.

In any of the various embodiments discussed herein, the reconstitutingsolution is a 0.9% saline solution.

In any of the various embodiments discussed herein, the pharmaceuticalbag is fabricated from a polyolefine/styrene-block copolymer based film.

In any of the various embodiments discussed herein, the pharmaceuticalbag withstands 121° Celsius.

In any of the various embodiments discussed herein, the pharmaceuticalbag withstands −55° Celsius.

In any of the various embodiments discussed herein, the second chamberfurther comprises an administration port for administering areconstituted pharmaceutical product that is a result of mixing thelyophilized pharmaceutical product and the reconstituting solution.

Some embodiments may include a flexible pharmaceutical bag may include afront film, a back film, an outer seal joining the front film to theback film around a perimeter of the pharmaceutical bag, and a breakableseal joining the front film and the back film interior of the outerseal, the breakable seal defining a first chamber and a second chamberseparated from the first chamber. The first chamber is configured tohold a lyophilized pharmaceutical product, the second chamber isconfigured to hold a reconstituting solution for reconstituting thelyophilized pharmaceutical product in the first chamber, and thebreakable seal breaks before the outer seal when a predetermined amountof pressure is applied to the flexible pharmaceutical bag.

In any of the various embodiments discussed herein, the first chamberand the second chamber are defined by the outer seal and the breakableseal.

It is to be appreciated that the Detailed Description section, and notthe Summary and Abstract sections, is intended to be used to interpretthe claims. The Summary and Abstract sections may set forth one or morebut not all exemplary embodiments of the present invention ascontemplated by the inventor(s), and thus, are not intended to limit thepresent invention and the appended claims in any way.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

What is claimed is:
 1. A flexible pharmaceutical bag comprising: a firstchamber configured to hold a lyophilized pharmaceutical product; asecond chamber separated from the first chamber; a third chamberseparated from one of the first and second chambers, the third chamberconfigured to hold a solution; a first seal disposed between the firstchamber and the second chamber that separates and seals the firstchamber from the second chamber; a second seal disposed between thethird chamber and one of the first and second chambers that seals thethird chamber from the first or the second chamber; and a first portattached to the first chamber, the first port configured to introduce apharmaceutical product into the first chamber and allow passage of watervapor from the pharmaceutical product during lyophilization of thepharmaceutical product.
 2. The pharmaceutical bag of claim 1, furthercomprising a second port attached to the second chamber, the second portconfigured to introduce a reconstituting solution to the second chamberfor reconstituting the lyophilized pharmaceutical product in the firstchamber.
 3. The pharmaceutical bag of claim 1, wherein the seal is aconnection between a front surface of the pharmaceutical bag and a backsurface of the pharmaceutical bag.
 4. The pharmaceutical bag accordingto claim 1, wherein the seal extends the length of the pharmaceuticalbag between the first chamber and the second chamber.
 5. Thepharmaceutical bag according to claim 1, wherein a predetermined amountof pressure applied to the pharmaceutical bag breaks the seal andconnects the second chamber to the first chamber.
 6. The pharmaceuticalbag according to claim 1, wherein the seal further comprises a weakpoint to provide an initial breaking point when a predetermined amountof pressure is applied to the pharmaceutical bag.
 7. The pharmaceuticalbag according to claim 1, wherein the pharmaceutical product is anantineoplastic, an immunomodulating agent, or a cytotoxic drug.
 8. Thepharmaceutical bag according to claim 1, wherein the pharmaceuticalproduct is selected from the group consisting of: azacytidine,belinostat, bendamustine, brentuximab vedotin, bleomycin, bortezomib,busulfan, carboplatin, carmustine, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, daunorubicin, decitabine, deferoxamine,doxorubicin, epirubicin hydrochloride, fludarabine, fotemustine,fulvestrant, gemcitabine, idarubicin, ifosfamide, irinotecanhydrochloride, ixabepilone, melphalan, methotrexate, oxaliplatin,paclitaxel, pemetrexed, pentostatin, raltitrexed, romidepsin,temozolomide, thiotepa, topotecan, trabectedin, trastuzumab, andvinblastine.
 9. The pharmaceutical bag according to claim 2, wherein thereconstituting solution is a 0.9% saline solution.
 10. Thepharmaceutical bag according to claim 1, wherein the pharmaceutical bagis fabricated from a polyolefine/styrene-block copolymer based film. 11.The pharmaceutical bag according to claim 1, wherein the pharmaceuticalbag withstands 121° Celsius.
 12. The pharmaceutical bag according toclaim 1, wherein the pharmaceutical bag withstands −55° Celsius.
 13. Thepharmaceutical bag according to claim 1, wherein one of the second andthird chambers is configured to hold a reconstituting solution forreconstituting the lyophilized pharmaceutical product in the firstchamber.
 14. The pharmaceutical bag according to claim 13, wherein thesecond chamber further comprises an administration port foradministering a reconstituted pharmaceutical product that is a result ofmixing the lyophilized pharmaceutical product and the reconstitutingsolution.
 15. A flexible pharmaceutical bag comprising: a first chamberconfigured to hold a lyophilized pharmaceutical product; a secondchamber separated from the first chamber, the second chamber configuredto hold a reconstituting solution for reconstituting the lyophilizedpharmaceutical product in the first chamber; a third chamber separatedfrom one of the first and second chambers, the third chamber configuredto hold a solution; a seal disposed between the first chamber and thesecond chamber that separates and seals the first chamber from thesecond chamber; and a first port attached to the first chamber, thefirst port configured to introduce a pharmaceutical product into thefirst chamber and allow passage of water vapor from the pharmaceuticalproduct during lyophilization of the pharmaceutical product, wherein thethird chamber is separated from one of the first and second chambers bya valve.
 16. The flexible pharmaceutical bag according to claim 15,wherein the valve is a one-way valve.
 17. The flexible pharmaceuticalbag according to claim 15, wherein the valve has a breakable seal.